Mutational Mechanisms in Multiply Relapsed Pediatric Acute Lymphoblastic Leukemia

Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. To determine which processes are active in (relapsed) ALL and how they behave during disease progression before and after therapy, we performed whole genome sequencing on tumor samples of 29 multiply relapsed ALL patients. Mutational load increased upon relapse in 28 patients and every subsequent relapse in 22 patients, with UV-like damage, APOBEC activity, reactive oxygen species, thiopurine-associated damage and an unknown therapy component driving mutagenesis. Thiopurines were the most prominent source of new mutations in relapse, affecting over half of the studied patients and causing potential relapse-driving mutations in multiple patients. Mutational processes often affected patients over longer time periods, but could also occur in isolated events, suggesting the requirement of additional triggers. Our data pose mutational processes as prominent secondary drivers with an important role in ALL development and progression.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001015401	Pediatric acute lymphoblastic leukemia (ALL) is marked by low mutational load at initial diagnosis, which increases at relapse. The elevated mutational load at relapse can partly be explained by at least two therapy-related effects and a combination of therapy and underlying mismatch repair deficiency. However, our understanding of the type and timing of mutational mechanisms in relapsed ALL is limited, and it is unclear to what extent mutational processes contribute to disease progression. We collected a cohort of 29 Dutch ALL patients across multiple treatment protocols who had multiple relapses. Using whole genome sequencing of the sequential tumor samples of each patient we were able to distinguish the mutational processes active in relapsed ALL and could track the activity of mutational processes over time. This allowed us to investigate whether subtype-specific mutational processes at diagnosis can continue in relapse or emerge at relapse if absent in initial diagnosis. Furthermore, we assessed whether the activity of mutational processes contributed to disease development and relapse.	Illumina NovaSeq 6000	135

Publications	Citations
Mutational mechanisms in multiply relapsed pediatric acute lymphoblastic leukemia. van der Ham CG, Suurenbroek LC, Kleisman MM, Antić Ž, Lelieveld SH, Yeong M, Westera L, Sonneveld E, Hoogerbrugge PM, van der Velden VHJ, van Leeuwen FN, Kuiper RP. Leukemia 38: 2024 2366-2375	0